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PHARMACOGENETICS OF MEMBRANE TRANSPORTERS Jeff Idle Institute of Pharmacology 1 st Faculty of Medicine Charles University, Praha.

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Presentation on theme: "PHARMACOGENETICS OF MEMBRANE TRANSPORTERS Jeff Idle Institute of Pharmacology 1 st Faculty of Medicine Charles University, Praha."— Presentation transcript:

1 PHARMACOGENETICS OF MEMBRANE TRANSPORTERS Jeff Idle Institute of Pharmacology 1 st Faculty of Medicine Charles University, Praha

2 Proc Natl Acad Sci USA 1915; 1:

3 PHARMACOGENETICS  HUNDREDS OR PROTEINS PARTICIPATE IN DRUG DISPOSITION  MOST, IF NOT ALL, DISPLAY GENETIC POLYMORPHISM  CRITICAL INTER-PATIENT VARIABILITY OCCURS WHEN DRUG LEVELS ARE TOO HIGH/LOW AT SITES OF ACTION  HISTORICALLY, THIS HAS BEEN ATTRIBUTED TO A FEW ENZYMES

4 PHARMACOKINETICS PROCESSENZYMESTRANSPORTERS ABSORPTION -++ DISTRIBUTION -+++ METABOLISM ++++ EXCRETION -+++

5 ROUTINE PHARMACOGENETICS  CYP2D6 AND ANTIDEPRESSANTS  CYP2C9 AND WARFARIN  TPMT AND AZATHIOPRINE/6-MP

6 DOSE ADJUSTMENT

7 EXAMPLES OF DOSE ADJUSTMENTS

8 TRANSPORTERS  30 years ago, drugs seen as subject only to passive diffusion from one compartment to another  pH, pKa (Henderson-Hasselbach equation) and MW (Fick’s Law of diffusion) were the guiding principles  Exceptions were amino acid absorption and renal excretion of a few drugs

9 TRANSPORTERS

10 SLC – SOLUTE TRANSPORTERS  PASSIVE TRANSPORT, COUPLED TRANSPORT AND EXCHANGE OF H +, Na +, K +, Ca 2+, Zn 2+, Cu 2+, Cl -, I -, PO 4 3-, HCO 3 -, Ach, GABA, choline, Nor, Dop, 5-HT, Gly, Tau, creatine, urea, folate, thiamine, moncarboxylates, dicarboxylates, citrate, ornithine, glutamate, aspartate, proline, neutral amino acids, cationic amino acids, bile acids, fatty acids, nucleosides, oligopeptides, glucose, organic cations, acetyl CoA, CMP-sialic acid, UDP-galactose, UDP- N-acetylglucosamine, UDP-glucuronic acid, UDP-N- acetylgalactosamine, glycerol-3-phosphate  AT PLASMA MEMBRANE, MITOCHONDRIAL MEMBRANE AND VESICULAR MEMBRANES

11 SLC TRANSPORTERS  SLC1A1-1A7, SLC2A1-2A14, SLC3A1-2, SLC4A1- 4A11, SLC5A1-5A12, SLC6A1-6A20, SLC7A1-7A14, SLC8A1-8A3, SLC9A1-9A11, SLC10A1-10A6, SLC11A1-11A2, SLC12A1-12A9, SLC13A1-13A5, SLC14A1-14A2, SLC15A1-15A4, SLC16A1-16A14, SLC17A1-17A8, SLC18A1-18A3, SLC19A1-19A3, SLC20A1-20A2, SLC22A1-22A18, SLC23A1-23A4, SLC24A1-24A6, SLC25A1-25A37, SLC26A1-26A11, SLC27A1-27A6, SLC28A1-28A3, SLC29A1-29A4, SLC30A1-30A9, SLC31A1-31A2, SLC32A1, SLC33A1, SLC34A1-34A3, SLC35A1-35A5, SLC35B1-35B4, SLC35C1-35C2, SLC35D1-35D3, SLC35E1-35E4, SLC35F1-35F5, SLC36A1-36A4, SLC37A1-37A4, SLC38A1-38A6, SLC39A1-39A14, SCL40A1, SCL41A1-41A3, SLC43A1-43A3

12 SLCO TRANSPORTERS  PREVIOUSLY GENE FAMILY SLC21  SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY  SLCO1A2, SLCO1B1, SLCO1B3, SLCO1C1, SLCO2A1, SLCO2B1, SLCO3A1, SLCO4A1, SLCO4C1, SLCO5A1, SLCO6A1

13 ABC (ATP-BINDING CASSETTE) TRANSPORTERS  ACTIVE EXPORT OF drugs and foreign chemicals  AT PLASMA MEMBRANES

14 ABC TRANSPORTERS  ABCA1-A13, ABCB1, ABCB4-B11, ABCC1- C6, ABCC8-C13, ABCD1-D4, ABCE1, ABCF1-F3, ABCG1-G5, ABCG8

15 SLC AND ABC TRANSPORTERS  SLC transporters  41 families  46 sub-families  316 members  Multiple cellular locations  Import, export, exchange  Wide range of endogenous and exogenous compounds  SLCO transporters  6 families  10 sub-families  11 members  Wide range of endogenous and exogenous anionic compounds  ABC transporters  1 family  6 sub-families  48 members  Plasma membrane  Export  Wide range of endogenous and exogenous compounds  TOTAL NUMBER OF TRANSPORTERS  375 members

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18 COMMON NAMES AND ASSOCIATIONS  ABCB1 Tangier disease  ABCA4 Stargardt disease (Juvenile macular degeneration)  ABCB1 Multidrug resistance 1 (MDR1)  ABCC7 Cystic fibrosis transmembrane conductance regulator (CFTR)  SLC2A1-5 GLUT1-5  SLC22A1-3OCT1-3  SLC22A6-10OAT1-5  SLC4A1Erythrocyte membrane protein band 3 (Diego blood group)  SLC6A4Serotonin transporter (SERT)

19 POLYMORPHISM OF TRANSPORTER FUNCTION GENETRANSPORTERDRUGS EFFECTS OF SINGLE NUCLEOTIDE POLYMORPHISMS REF. SLC29A1ENT1 Nucleoside analogues Haplotypes do not alter uptake of Ribovirin, Cytarabine, 5- Fluorouridine Osato et al. (2003) SLC6A2NET1Noradrenaline SNP (0.07%) causes reduced affinity for Nor Runkel et al. (2000) Paczkowski et al. (2002) SLC22A2OCT2ProcainamideCimetidineMetformin, Quinidine Quinidine Four SNPs reduce renal elimination Leabman et al. (2002) SLCO1B1OATP1B1Pravastatin 17  -estradiol-17  - D-glucuronide SNP markedly reduces non-renal clearance Iwai et al. (2004) SLC18A2VMAT2 Reserpine (inhibitor of amine uptake) Two rare SNPs alter reserpine inhibition Burman et al. (2004)

20 POLYMORPHISM OF TRANSPORTER FUNCTION GENETRANSPORTERDRUGS EFFECTS OF SINGLE NUCLEOTIDE POLYMORPHISMS REF. SLCO1B3OATP1B3Digoxin 17  -estradiol-17  - D-glucuronide Taurocholate Bile acid transport abolished by 2 SNPs. Letschert et al. (2004) SLC6A4SERT5-HT Haplotype associated with Bipolar Affective Disorder (Taiwan) Sun et al. (2004) SLC22A1OCT1 MPP + 5-HT SNPs alter substrate specificity of OCT1 Kerb et al. (2002) ABCB1MDR1CyclosporineTacrolimus (calcineurin inhibitors) 2677TT genotype associated with reduced risk of renal dysfunction Herbert et al. (2003) ABCB1MDR1Loperamide±Quinidine 2677G/3435T haplotype associated with higher plasma concentrations Skarke et al. (2003)

21 PERSPECTIVE  SLC, SLCO, and ABC transporters play a critical role in drug pharmacokinetics, affecting absorption, hepatic uptake, hepatic export, tissue distribution, and renal and biliary elimination.  A body of unstructured pharmacogenetic data is rapidly accumulating that suggests strongly that membrane transporters are subject to both genotypic and phenotypic polymorphism.

22 PERSPECTIVE  Genetically-determined variability in drug and hormone transporter function may explain major inter-patient variability in drug pharmacokinetics and susceptibility to drug resistance and toxicity.  These differences may be greater than those due to the known enzyme polymorphisms.  There is much to do.


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